The spectrum of nonalcoholic fatty liver disease (NAFLD) includes steatosis, nonalcoholic steatohepatitis (NASH) and cirrhosis;and multiple metabolic impairments including disruption of endoplasmic reticulum (ER) homeostasis. Disruption of ER homeostasis or ER stress activates the unfolded protein response (UPR). Recent studies performed in obese, nondiabetic humans with NAFLD have observed activation of the UPR in liver and/or adipose tissue. The trigger(s) for ER stress in the liver and how ER homeostasis is linked to disease progression in NAFLD have not been determined. An additional issue in NAFLD involves identification of cellular and molecular events that change the disease from non-progressive steatosis to NASH and progressive liver disease. One cellular event that appears to be a cardinal feature of NASH is hepatocyte apoptosis. Our work over the last 4 yrs has demonstrated that delivery of long chain saturated fatty acids to liver cells or increasing the amount of saturated fatty acids within the liver provokes ER stress, apoptosis and liver injury. These studies have lead to the hypothesis that the composition of fatty acids delivered to or stored within the liver is an important determinant of ER homeostasis, hepatocyte apoptosis and disease progression in NAFLD. The focus of this application is to elucidate how saturated fatty acids disrupt ER homeostasis and to identify cellular mechanisms that link ER homeostasis to hepatocyte apoptosis and liver injury. Towards this end, the following specific aims are proposed: 1) To determine how saturated fatty acids promote ER stress, apoptosis and liver injury in vivo, 2) To determine whether saturated fatty acid-mediated ER stress, apoptosis and liver injury involves impairments in protein chaperone function, and 3) To identify cellular mechanisms linking saturated fatty acids and hepatocyte apoptosis using cell models. PUBLIC HEALTH RELEVANCE: Fatty liver disease is poorly understood and the factors that promote liver damage in this disease have not been identified. This application investigates the hypothesis that the amount of saturated fatty acids delivered to or stored within the liver is an important factor in disease progression.